(a) Technical Field
The present invention relates to an siRNA inhibiting expression of OTUB1 and a pharmaceutical composition containing same.
(b) Background Art
Division, growth, differentiation and necrosis of cells are regulated by complicated processes and abnormality of these processes leads to cancer owing to unregulated cell proliferation. In particular, abnormality of cell division is thought as the direct cause of cancer and substances that regulate cell division are considered as targets for prevention and treatment of cancer.
Cell division occurs during the cell cycle consisting of G1, S, G2 and M phases. A checkpoint exists in each phase and regulates the progress of the cell cycle. The activity of the proteins involved in the regulation of the cell cycle is mainly controlled through phosphorylation by kinases and degradation by ubiquitination.
Together with ubiquitination, deubiquitination also plays an important role in the regulation of cell division. Usp44 regulates anaphase initiation by deubiquitinating cdc20 (Stegmeier F, Rape M, Draviam V M, et al. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 2007; 446: 87681) and Usp1 and Usp7 are known to regulate DNA damage checkpoint (Nijman S M, Huang T T, Dirac A M, et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 2005; 17: 3319, Huang T T, Nijman S M, Mirchandani K D, et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol 2006; 8: 33947). Also, Usp7 is known to regulate stabilization of p53 by deubiquitinating Mdm2 (Brooks C L, Li M, Hu M, Shi Y, Gu W. The p53-Mdm2-HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 2007; 26: 72626) and Usp16 is known to regulate chromosomal segregation during mitosis by deubiquitinating histone H2A (Joo H Y, Zhai L, Yang C, et al. Regulation of cell cycle progression and gene expression by H2A deubiquitination. Nature 2007; 449: 106872).
Ovarian tumor domain-containing proteases (OTUs) are one of deubiquitinating enzyme families. The OTU family includes OTUB1, OTUB2, A20, etc. and shares the OTU domain consisting of 130 amino acids. OTUB1 is the first known member of the OTU family proteins and is known to be uniformly distributed in all tissues. Unlike other deubiquitinating enzymes, OTUB1 is reported to inhibit DNA damage in a non-catalytic manner by binding to the E2 enzyme UBC13 rather than directly deubiquitinating its substrate (Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang Y C, O'Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras A C, Natsume T, Suda T, Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 2010 Aug. 19; 466 (7309): 941-6). It is also reported to regulate deubiquitinating enzymes by binding to UbcH5, UBE2D and UBE2E (Juang Y C, Landry M C, Sanches M, Vittal V, Leung C C, Ceccarelli D F, Mateo A R, Pruneda J N, Mao D Y, Szilard R K, Orlicky S, Munro M, Brzovic P S, Klevit R E, Sicheri F, Durocher D. OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme function. Mol Cell 2012 Feb. 10; 45 (3): 384-97). As such, although researches on the function of OTUB1 are reported recently, there are few reports on its direct relationship with cancer.
The inventors of the present invention have found that the expression of the OTUB1 protein is remarkably increased in lung cancer cells when compared to in normal lung cells and inhibition of OTUB1 in the lung cancer cells with siRNA leads to inhibited cell growth.
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present invention.